The mammalian immune response is based on a series of complex cellular interactions, called the “immune network”. Recent research has provided new insights into the inner workings of this network. While it remains clear that much of the response does, in fact, revolve around the network-like interactions of lymphocytes, macrophages, granulocytes, and other cells, immunologists now generally hold the opinion that soluble proteins, known as cytokines play a critical role in controlling these cellular interactions. Thus, there is considerable interest in the isolation, characterization, and mechanisms of action of cell modulatory factors, an understanding of which will lead to significant advancements in the diagnosis and therapy of numerous medical abnormalities, e.g., immune system disorders. Some of these factors are hematopoietic growth and/or differentiation factors, e.g., stem cell factor (SCF) or IL-12 (see, e.g., Mire-Sluis and Thorpe (1998) Cytokines, Academic Press, San Diego, Calif.; Thomson (ed.) (1998)The Cytokine Handbook (3d ed.) Academic Press, San Diego, Calif.; Metcalf and Nicola (1995) The Hematopoietic Colony Stimulating Factors, Cambridge Univ. Press, Cambridge, UK; and Aggarwal and Gutterman (1991) Human Cytokines, Blackwell, Malden, Mass.).
Cytokines mediate cellular activities in a variety of ways. They have been shown to support the proliferation, growth, and differentiation of pluripotential hematopoietic stem cells into large numbers of progenitors comprising diverse cellular lineages making up a complex immune system. Proper and balanced interactions between the cellular components are necessary for a healthy immune response. The different cellular lineages often respond in a different manner when cytokines are administered in conjunction with other agents.
Cell lineages especially important to the immune response include: B-cells, which can produce and secrete immunoglobulins (proteins with the capability of recognizing and binding to foreign matter to effect its removal), T-cells of various subsets that secrete cytokines and induce or suppress the B-cells and various other cells (including other T-cells) making up the immune network, NK cells, which are responsible for cytokine production in response to infectious agents and tumor cells, and antigen presenting cells such as dendritic and other myeloid derived cells.
The present invention provides methods of using IL-27, a cytokine related to IL-12. IL-12 plays a critical role in cell-mediated immunity. Its activities are triggered through a high-affinity receptor complex comprising two subunits, IL-12Rbeta1 and IL-12Rbeta2. The p35 subunit of IL-12 can bind to a second soluble protein called EBI3, and it was suggested that p35 and EBI3 form a secreted heterodimer, though the function of this heterodimer is unclear. EBI3 also binds to another protein, p28, to form a soluble heterodimer comprising p28 and EBI3, now called IL-27. The p28 subunit is also known as IL-80 or IL-D80. A cDNA encoding the human and mouse p35 subunit has been described in US20020164609 and WO 02/068596, both of which are incorporated by reference (see, e.g., Devergne, et al. (1997) Proc. Natl. Acad. Sci. USA 94:12041-12046; Chua, et al. (1995) J. Immunol. 155:4286:4294; Presky, et al. (1998) J. Immunol. 160:2174-2179; Gately, et al. (1998) Ann. Rev. Immunol. 16:495-521; Presky, et al. (1996) Proc. Natl. Acad. Sci. USA 93:14002-14007; Trinchieri (1998) Adv. Immunol. 70:83-243; Trinchieri (1998) Immunol. Res. 17:269-278; Trinchieri (1995) Annu. Rev. Immunol. 13:251-276).
The present invention provides methods to modulate expression of interferon-gamma (IFNgamma) for the purpose of stimulating immune defense against bacteria and parasites, e.g., intracellular bacteria and parasites, and against viruses, cancers, and tumors. IFNgamma can mediate immune response against intracellular bacteria, where common intracellular bacterial species include Salmonella sp., Shigella sp., Listeria sp., Francisella sp., Mycobacteria sp. (tuberculosis; leprosy), Legionella sp., Rickettsia sp., Orienta sp., Ehrlichia sp., Anaplasma sp., Neorickettsia sp., Chlamydia sp., and Coxiella sp. Additionally, IFNgamma mediates response to parasites, e.g., Plasmodia sp. (malaria), Toxoplasma sp., Leishmania sp., Trypanosonia sp., and Cryptosporidium sp. Moreover, IFNgamma mediates immune defense against viruses, e.g., HIV, orthopoxviruses, such as variola virus and vaccinia virus (smallpox), and herpesviruses, including alphaherpesviruses, e.g., Herpes Simplex virus, and betaherpesviruses, e.g., Cytomegalovirus. Also provided are methods of reducing or inhibiting IFNgamma expression, e.g., for the treatment of chronic inflammatory disorders, such as Crohn's disease (see, e.g., Kent, et al. (2000) Vaccine 18:2250-2256; Ismail, et al. (2002) FEMS Microbiol. Lett. 207:111-120; Kaufmann (2001) Nature Revs. Immunol. 1:20-30; Goebel and Gross (2001) TRENDS Microbiol. 9:267-273; Heussler, et al. (2001) Int. J. Parasitol. 31:1166-1176; Luder, et al. (2001) Carsten, et al. (2001) TRENDS Parasitol. 17:480-486; Rook, et al. (2001) Eur. Resp. J. 17:537-557; Stenger and Rollinghoff (2001) Ann. Rheum. Dis. 60:iii43-iii46; Haas, et al. (2002) Am. J. Dermatopathol. 24:319-323; Dorman and Holland (2000) Cytokine Growth Factor Revs. 11:321-333; Smith, et al. (2002) J. Gen. Virol. 83 (Pt. 12) 2915-2931; Cohrs and Gilden (2001) Brain Pathol. 11:465-474; Tannenbaum and Hamilton (2002) Sem. Cancer Biol. 10:113-123; Ikeda, et al. (2002) Cytokine Growth Factor Revs. 13:95-109; Klimp, et al. (2002) Crit. Rev. Oncol. Hematol. 44:143-161; Frucht, et al. (2001) TRENDS Immunol. 22:556-560).
From the foregoing, it is evident that discoveries of new functions and methods relating to cytokines and cytokine receptors, e.g., relating to IL-27, IL-12, and their receptors, can contribute to new therapies for a wide range of degenerative or abnormal conditions, e.g., infections and cancers, where the therapies directly or indirectly involve the immune system and/or hematopoietic cells. In particular, the discovery and development of cytokines which enhance or potentiate the beneficial activities of known cytokines would be highly advantageous. The present invention provides methods of enhancing IFNgamma production using IL-27.